4B5D

Capitella teleta AChBP in complex with psychonicline (3-((2(S)- Azetidinyl)methoxy)-5-((1S,2R)-2-(2-hydroxyethyl)cyclopropyl)pyridine)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.19 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.194 

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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Insights Into the Structural Determinants Required for High- Affinity Binding of Chiral Cyclopropane-Containing Ligands to Alpha4Beta2-Nicotinic Acetylcholine Receptors: An Integrated Approach to Behaviorally Active Nicotinic Ligands.

Zhang, H.Eaton, J.B.Yu, L.Nys, M.Mazzolari, A.Van Elk, R.Smit, A.B.Alexandrov, V.Hanania, T.Sabath, E.Fedolak, A.Brunner, D.Lukas, R.J.Vistoli, G.Ulens, C.Kozikowski, A.P.

(2012) J Med Chem 55: 8028

  • DOI: https://doi.org/10.1021/jm3008739
  • Primary Citation of Related Structures:  
    4B5D

  • PubMed Abstract: 

    Structure-based drug design can potentially accelerate the development of new therapeutics. In this study, a cocrystal structure of the acetylcholine binding protein (AChBP) from Capitella teleta (Ct) in complex with a cyclopropane-containing selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonist (compound 5) was acquired. The structural determinants required for ligand binding obtained from this AChBP X-ray structure were used to refine a previous model of the human α4β2-nAChR, thus possibly providing a better understanding of the structure of the human receptor. To validate the potential application of the structure of the Ct-AChBP in the engineering of new α4β2-nAChR ligands, homology modeling methods, combined with in silico ADME calculations, were used to design analogues of compound 5. The most promising compound, 12, exhibited an improved metabolic stability in comparison to the parent compound 5 while retaining favorable pharmacological parameters together with appropriate behavioral end points in the rodent studies.


  • Organizational Affiliation

    Drug Discovery Program, Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CAPITELLA TELETA ACHBP
A, B, C, D, E
230Capitella teletaMutation(s): 0 
UniProt
Find proteins for I6L8L2 (Capitella teleta)
Explore I6L8L2 
Go to UniProtKB:  I6L8L2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupI6L8L2
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose
F, G
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G42666HT
GlyCosmos:  G42666HT
GlyGen:  G42666HT
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
SW4 Binding MOAD:  4B5D Ki: 12.8 (nM) from 1 assay(s)
PDBBind:  4B5D Ki: 12.8 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.19 Å
  • R-Value Free: 0.242 
  • R-Value Work: 0.191 
  • R-Value Observed: 0.194 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.359α = 90
b = 114.284β = 90
c = 135.793γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-09-26
    Type: Initial release
  • Version 1.1: 2012-10-10
    Changes: Database references
  • Version 1.2: 2019-04-24
    Changes: Data collection, Derived calculations, Other, Source and taxonomy
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Other, Structure summary
  • Version 2.1: 2023-12-20
    Changes: Data collection, Database references, Refinement description, Structure summary